Sex Differences in Liver Toxicity—Do Female and Male Human Primary Hepatocytes React Differently to Toxicants In Vitro?

There is increasing amount of evidence for sex variation in drug efficiency and toxicity profiles. Women are more susceptible than men to acute liver injury from xenobiotics. In general, this is attributed to sex differences at a physiological level as well as differences in pharmacokinetics and pharmacodynamics, but neither of these can give a sufficient explanation for the diverse responses to xenobiotics. Existing data are mainly based on animal models and limited data exist on in vitro sex differences relevant to humans. To date male and female human hepatocytes have not yet been compared in terms of their responses to toxicants. We investigated whether sex-specific differences in acute hepatotoxicity can be observed in vitro at a cellular level by comparing hepatotoxic drug effects in male and female primary human hepatocytes. Significant sex-related differences were found for particular parameters and individual drugs showing that the tested substances are more toxic to female hepatocytes. Moreover, our work demonstrated that high content screening is feasible with pooled primary human hepatocytes in suspension.JRC.I.5-Systems Toxicolog

Evaluation of the availability and applicability of computational approaches in the safety assessment of nanomaterials: Final report of the Nanocomput project

This is the final report of the Nanocomput project, the main aims of which were to review the current status of computational methods that are potentially useful for predicting the properties of engineered nanomaterials, and to assess their applicability in order to provide advice on the use of these approaches for the purposes of the REACH regulation. Since computational methods cover a broad range of models and tools, emphasis was placed on Quantitative Structure-Property Relationship (QSPR) and Quantitative Structure-Activity Relationship (QSAR) models, and their potential role in predicting NM properties. In addition, the status of a diverse array of compartment-based mathematical models was assessed. These models comprised toxicokinetic (TK), toxicodynamic (TD), in vitro and in vivo dosimetry, and environmental fate models. Finally, based on systematic reviews of the scientific literature, as well as the outputs of the EU-funded research projects, recommendations for further research and development were also made. The Nanocomput project was carried out by the European Commission’s Joint Research Centre (JRC) for the Directorate-General (DG) for Internal Market, Industry, Entrepreneurship and SMEs (DG GROW) under the terms of an Administrative Arrangement between JRC and DG GROW. The project lasted 39 months, from January 2014 to March 2017, and was supported by a steering group with representatives from DG GROW, DG Environment and the European Chemicals Agency (ECHA).JRC.F.3-Chemicals Safety and Alternative Method

Seurat-1: HepaRG, repeated and single dose exposure for Mitochondrial Health and LipidTox

The purpose of this report is to describe the experimental procedure used in order to detect changes in mitochondrial membrane potential and lipid accumulation following exposure of HepaRG cells to various chemicals both by repeated exposure as single exposure to chemicals. This procedure was created for the SEURAT-1 Project runs 15 to 18 and was developed by using live cell imaging.JRC.I.5-Systems Toxicolog

Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

JRC.I.5-Systems Toxicolog

A high throughput imaging database of toxicological effects of nanomaterials tested on HepaRG cells

The large amount of existing nanomaterials demands rapid and reliable methods for testing their potential toxicological effect on human health, preferably by means of relevant in vitro techniques in order to reduce testing on animals. Combining high throughput workflows with automated high content imaging techniques allows deriving much more information from cell-based assays than the typical readouts (i.e. one measurement per well) with optical plate-readers. We present here a dataset including data based on a maximum of 14 different read outs (including viable cell count, cell membrane permeability, apoptotic cell death, mitochondrial membrane potential and steatosis) of the human hepatoma HepaRG cell line treated with a large set of nanomaterials, coatings and supernatants at different concentrations. The database, given its size, can be utilized in the development of in silico hazard assessment and prediction tools or can be combined with toxicity results from other in vitro test systems.peer-reviewe

EURL ECVAM Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2016)

Replacement, Reduction and Refinement of animal testing is anchored in EU legislation. Alternative non-animal approaches facilitate a shift away from animal testing. Cell-based methods and computational technologies are integrated to translate molecular mechanistic understanding of toxicity into safety testing strategies.JRC.F.3-Chemicals Safety and Alternative Method

Hiki, ähky ja loikka - Osallistujien pedagogisia mietteitä ja ideoita hankkeen varrelta

DIGIJOUJOU-hankkeessa työskennelleet opettajat ovat hankkeen toimintavuosien 2017-2019 aikana pohtineet opetuksen ja oppimisen digitaalisuutta ja joustavuutta eri näkökulmista: mitä digitaalisuus ja joustavuus suomen ja ruotsin opiskelussa tarkoittaa, miten soveltaa, lisätä ja kehittää digitaalisuutta ja joustavuutta omassa opetuksessa ja opiskelijoiden oppimisessa. Hankelaisten blogikirjoituksissa näemme askeleita opettajien omasta ja yhdessä muiden kanssa oppimisesta hankkeen edetessä; epävarmuus muuttuu varmuudeksi, ajoittainen digiähky oman asiantuntijuuden kasvuksi ja joustavuus osaksi opettajan arkipedagogiikkaa. Antoisia ja inspiroivia lukuhetkiä! Lisätietoa: https://digijoujou.aalto.fi/Lärarna i DIGIJOUJOU-projektet har under projektets verksamhetsår 2017-2019 reflekterat över digitalisering och exibilitet från olika perspektiv; vad betyder digitalisering och exibilitet i lärandet av finska och svenska, hur ska man implementera, öka och utveckla dessa i den egna undervisningen och i hur studerande lär sig finska och svenska. I projektdeltagarnas bloginlägg får vi inblick i hur allas lärandeprocess i projektet framskrider; osäkerhet utvecklas till säkerhet, digikaoset får ordning och exibilitet blir en del av den egna sakkunnigheten och pedagogiken. Med önskan om givande och inspirerande läsning! Mer information: https://digijoujou.aalto.fi

Low Frequency Stimulation and Resulting Short Term Effects on Neuronal Activity

Ex vivo cultured networks of neurons coupled to Micro Electrode Arrays (MEAs) constitute a valuable tool for experimentally investigating changes in neuronal dynamics at different developmental stages and in response to xenobiotic exposure. Spike trains as well as bursts can be easily extracted from background noise and thus it is straightforward to evaluate changes in activity in response to external manipulation. These devices make it possible to record the firing activity of neurons over very long periods of time, even months, and it is possible to follow up the functional development by means of the electrophysiology generated form isolated neurons (i.e. first days) up to fully connected neuronal networks (third week) and that reflects phases of massive overproduction of synaptic connections and subsequent synaptic elimination and stabilization. The longitudinal recordings presented here reveal characteristic changes in firing activity of the developing networkJRC.I.6-Systems toxicolog

Autofluorescence microscopy: a non-destructive tool to monitor mitochondrial morphology and toxicity

Visualization of NADH by fluorescence microscopy makes it possible to distinguish mitochondria inside living cells allowing structure analysis of these organelles in a noninvasive way. Mitochondrial morphology is determined by the occurrence of mitochondrial fission and fusion. During normal cell function mitochondria appear as elongated tubular structures. However cellular malfunction induce mitochondria to fragment into punctiform, vesicular structures. This change in morphology has also been associated with the generation of reactive oxygen species (ROS) and early apoptosis. In this study we demonstrated that autofluorescence imaging of mitochondria in living eukaryotic cells provides structural and morphological information that can be used to describe mitochondrial health. We firstly established the illumination conditions that do not affect mitochondrial structure and calculated the maximum safe light dose that the cells can be exposed to. Subsequently we showed that by sequential recording of mitochondrial fluorescence it is possible to monitor changes in mitochondrial morphology in a continuous non-destructive way. This approach was then applied to describe mitochondrial toxicity induced by potential toxicants exposed to mammalian cells. Both mouse and human cells were used to evaluate mitochondrial toxicity of different compounds with different toxicities. It has been proven in this study that this technique constitutes a novel approach to explore chemical induced toxicity due to its reliability to monitor mitochondrial morphology changes and corresponding toxicity in a non-invasive way.JRC.I.6-Systems toxicolog